Is a history of prostate cancer a contraindication to testosterone (testosterone) therapy in patients with low testosterone levels?

Testosterone Therapy in Men with a History of Prostate Cancer

A history of prostate cancer is no longer considered an absolute contraindication to testosterone therapy in carefully selected men who have been definitively treated for low-risk disease and show no evidence of active cancer, though FDA labeling still lists it as a contraindication. 1, 2, 3

The Evolving Guideline Landscape

There is a clear disconnect between FDA drug labeling and current clinical evidence:

• FDA labels for testosterone products explicitly list "known or suspected carcinomas of the prostate" as a contraindication 2, 3
• However, the New England Journal of Medicine notes that "a history of prostate cancer has been considered an absolute contraindication to testosterone-replacement therapy, this point is now under active debate for men who are deemed cured" 4
• The American Urological Association acknowledges that "there are a large percentage of men in need of testosterone therapy who fail to receive it due to clinician concerns, mainly surrounding prostate cancer development...although current evidence fails to definitely support these concerns" 4

Patient Selection Criteria for Consideration

Testosterone therapy can be cautiously considered only in men meeting ALL of the following criteria: 1

• Definitively treated prostate cancer with radical prostatectomy showing favorable pathology: negative margins, negative seminal vesicles, negative lymph nodes, and undetectable PSA 1
• Documented biochemical hypogonadism with two separate morning testosterone measurements below 300 ng/dL 4
• Symptomatic testosterone deficiency affecting quality of life 4
• No evidence of active disease or biochemical recurrence 1

The Evidence Supporting Cautious Use

Prospective studies demonstrate low rates of cancer detection during testosterone therapy, with only 5 cases among 461 men (1.1%) followed for 6-36 months—similar to the general population prevalence 4

In a review of 111 men with prior prostate cancer treatment (radical prostatectomy, external beam radiation, or brachytherapy) who received testosterone therapy, only 2 biochemical recurrences (1.8%) were observed 5

The saturation model explains why testosterone therapy may be safer than historically believed: prostate cancer is exquisitely sensitive to testosterone changes at LOW concentrations (castrate levels), but becomes androgen-indifferent at higher concentrations due to finite androgen receptor binding capacity 5

Critical Monitoring Requirements

If testosterone therapy is initiated in a man with treated prostate cancer, intensive surveillance is mandatory: 1

• PSA monitoring every 3 months for the first year, then every 6 months if stable 1
• Immediate discontinuation if PSA rises >0.2 ng/mL on two consecutive measurements 1
• Urologic referral if PSA increases >1.0 ng/mL in the first 6 months or >0.4 ng/mL per year thereafter 6
• Hematocrit monitoring every 3 months initially, with therapy withheld if hematocrit exceeds reference range 6

High-Risk Features That Preclude Therapy

Testosterone therapy should NOT be offered to men with: 1

• High-risk prostate cancer features (positive margins, seminal vesicle invasion, lymph node involvement) 1
• Detectable or rising PSA after definitive treatment 1
• Metastatic disease or active cancer 2, 3

The Quality of Life Consideration

Worrisome features of prostate cancer such as high Gleason score, extracapsular disease, and biochemical recurrence have been reported in association with LOW testosterone levels, not high levels 5

Low pretreatment testosterone may be associated with worse oncological outcomes, with one study showing a trend toward decreased overall survival (83.9% vs. 91.3%) in men with baseline low testosterone who also received androgen deprivation therapy 7

Common Pitfalls to Avoid

• Do not initiate therapy without two confirmatory morning testosterone measurements showing levels <300 ng/dL 4
• Do not proceed without thorough discussion of the off-label nature of this use given FDA contraindications 2, 3
• Do not use testosterone therapy in men with untreated or active prostate cancer 2, 3
• Do not fail to establish rigorous PSA monitoring protocols before starting therapy 1

The Bottom Line for Clinical Practice

While FDA labeling prohibits testosterone use in men with prostate cancer, emerging evidence suggests carefully selected men with definitively treated, low-risk disease may be candidates for therapy under intensive surveillance. 4, 1 This requires shared decision-making, acknowledgment of off-label use, and commitment to rigorous monitoring protocols. 1 Men with high-risk features, detectable PSA, or active disease remain absolute contraindications. 1, 2, 3